Methods of treating and preventing congestive heart failure with hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate

ABSTRACT

The present invention provides methods of treating and preventing mortality associated with heart failure in an African American patient with hypertension, and improving oxygen consumption, quality of life and exercise tolerance by administering a therapeutically effective amount of at least one hydralazine compound and at least one of isosorbide dinitrate and isosorbide mononitrate, and, optionally, one or more compounds, such as, for example, a digitalis, a diuretic compound, or a compound used to treat cardiovascular diseases. In the present invention, the hydralazine compound is preferably hydralazine or a pharmaceutically acceptable salt thereof. Preferred methods of the invention comprise administering hydralazine or a pharmaceutically acceptable salt thereof and isosorbide dinitrate.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. application Ser. No.09/658,261 filed Sep. 8, 2000, which claims priority to U.S. applicationSer. No. 60/171,102 filed Dec. 16, 1999, and to U.S. application Ser.No. 60/152,616 filed Sep. 8, 1999.

FIELD OF THE INVENTION

[0002] The present invention provides methods of treating and preventingmortality associated with heart failure, improving oxygen consumption,quality of life and/or exercise tolerance in a black patient, withhypertension by administration of a therapeutically effective amount ofat least one hydralazine compound or a pharmaceutically acceptable saltthereof, and at least one of isosorbide dinitrate and isosorbidemononitrate, and, optionally, one or more compounds, such as, forexample, a digitalis, a diuretic compound, and/or a compound used totreat cardiovascular diseases.

BACKGROUND OF THE INVENTION

[0003] Heart failure in black patients has been associated with a poorerprognosis than in white patients. In diseases such as hypertension,blacks exhibit pathophysiologic differences and respond differently tosome therapies than whites.

[0004] Congestive heart failure (CEF) is a clinical syndrome involvingcardiac and peripheral abnormalities that produce morbidity andshortened life span. This syndrome is now the leading cause ofhospitalization in individuals older than age 65 and is a majorcontributor to the escalation of heath care costs. Recent reports byGhali et al (Arch. Intern. Med. 150:769-773 (1990)) and Alexander et al(JAMA, 274(13):1037-1042 (1995)) have suggested that black patients mayhave a greater risk than white patients of developing heart failure thatconsumes medical resources (Whittle et al., N. Engl. J. Med.,329:621-627 (1993)), and the population-based mortality rate for heartfailure has been reported to be significantly higher in blacks (Gillum,Am. Heart J., 113: 1043-1045 (1987)).

[0005] Vasodilator-Heart Failure Trials (V-HeFT) have been conducted,and the trials' designs and results have been published previously (Cohnet al, N. Engl. J. Med., 314:1547-1552 (1986); Cohn et al, N. Engl. J.Med. 325:303-310 (1991)). V-HeFT I was conducted between 1980 and 1985,prior to the introduction of ACE inhibitor therapy. V-HeFT II wasconducted from 1985 to 1990. V-HeFT I and V-HeFT II did not consider therace or ethnic origin of the patients that participated in the studies.

[0006] Cardiovascular disease may, however, affect white and blackpatients differently. For example, hypertension, a major etiology ofheart failure in black patients, differs pathophysiologically and intreatment response between racial groups (Gillum, Hypertension,1:468-475 (1979)). No data at present have examined whether similardifferences exist between black patients and white patients with heartfailure.

[0007] There is a need in the art for new and more effectivecompositions and methods for treating and preventing mortalityassociated with heart failure in black patients with hypertension. Thepresent invention is directed to these, as well as other, importantends.

SUMMARY OF THE INVENTION

[0008] The present invention provides methods for treating andpreventing mortality associated with heart failure, improving oxygenconsumption, quality of life and/or exercise tolerance in non-Caucasianpatients, preferably black patients, with hypertension by administeringa therapeutically effective amount of at least one hydralazine compoundor a pharmaceutically acceptable salt thereof, and at least one ofisosorbide dinitrate and isosorbide mononitrate, and, optionally, one ormore compounds, such as, for example, a digitalis, a diuretic compound,and/or a compound used to treat cardiovascular diseases. The hydralazinecompound is preferably hydralazine, or a pharmaceutically acceptablesalt thereof, such as hydralazine hydrochloride. The hydralazinecompound and the isosorbide dinitrate or isosorbide mononitrate can beadministered separately or as components of the same composition.

[0009] These and other aspects of the present invention are described inmore detail below.

BRIEF DESCRIPTION OF THE FIGURES

[0010]FIG. 1 shows the racial difference in mortality in the placebogroup in V-HeFT I. White and black patients exhibited similar survival(White, n=192; Black, n=79).

[0011]FIG. 2 shows the effects of treatment with hydralazine andisosorbide dinitrate on survival in V-HeFT I.

[0012]FIG. 2A shows the benefit of hydralazine-isosorbide dinitrate inblack patients (HI) (placebo, n=79; HI, n=49; prazosin, n=52);

[0013]FIG. 2B shows an absence of demonstrable treatment benefit inwhite patients (placebo, n=192; HI, n=132; prazosin, n=127).

[0014]FIG. 3 shows the racial difference in the effect of treatment onmortality in V-HeFT II.

[0015]FIG. 3A shows that enalapril and hydralazine-isosorbide dinitrateexhibit similar survival curves in black patients (enalapril, n=106; HI,n=109);

[0016]FIG. 3B shows that enalapril exerts significant survival benefitin white patients (enalapril, n=292; HI, n=282).

[0017]FIG. 4 demonstrates the influence of history of hypertension onthe effect of therapy on survival in V-HeFT II.

[0018]FIG. 4A and FIG. 4B show the mortality of white patients with andwithout a hypertensive history, respectively.

[0019]FIG. 4C and FIG. 4D show the mortality of black patients with andwithout a hypertensive history, respectively. The benefit of enalaprilcompared to hydralazine-isosorbide dinitrate was most apparent in whitepatients with a hypertensive history. Details of the patient populationare shown in Table 3.

[0020]FIG. 5 shows the change in systolic blood pressure frompre-randomization level in V-HeFT II. Enalapril exerted a greater andmore sustained blood pressure reduction in white than in black patients.The hydralazine-isosorbide dinitrate combination did not significantlyreduce blood pressure in either racial group.

[0021]FIG. 6 shows the change in ejection fraction (EF) in V-HeFT II. EFtended to rise in all treatment groups; significant increases frombaseline (p<0.05) are depicted by filled symbols. Increase of EF inblack patients treated with enalapril tended to be less prominent.

[0022]FIG. 7 shows the change in peak exercise oxygen consumption(maximal VO₂) in V-HeFT II. Hydralazine-isosorbide dinitrate produced anearly (6 months) increase in exercise capacity and the enalapril groupexhibited a more prominent decline in exercise capacity over time (1-4.5years).

[0023]FIG. 8 shows the change in plasma norepinephrine (PNE) in V-HeFTII. Norepinephrine rose in the first year in response tohydralazine-isosorbide in both racial groups but not in the enalaprilgroups. Thereafter PNE increased similarly in all treatment groups.

[0024]FIG. 9 shows the change in cardiothoracic ratio in (CTR) in V-HeFTII. Significant sustained reduction was apparent only in white patientstreated with enalapril.

DETAILED DESCRIPTION OF THE INVENTION

[0025] In the present invention, the results of the firstVasodilator-Heart Failure Trial (V-HeFT I) were reexamined andreevaluated, and the baseline characteristics, prognosis, and responseto therapy for 180 black male patients and 450 white male patients werecompared. V-HeFT II was also reexamined and reevaluated in the presentinvention, and the same comparisons were made for 215 black malepatients and 574 white male patients, including an analysis stratifiedby the presence or absence of a history of hypertension. It has now beendiscovered that in both V-HeFT I and II, black patients had a lowerincidence of coronary artery disease, more previous hypertension, and alarger cardiothoracic ratio (p<0.05) than white patients. In V-HeFT II,plasma norepinephrine was significantly lower in blacks; and plasmarenin activity was lower only in blacks with a history of hypertension.Overall mortality or congestive heart failure hospitalization did notdiffer between blacks and whites in the placebo group in V-HeFT I.

[0026] It has now been unexpectedly discovered that the mortality ofblack patients is significantly reduced, and that their oxygenconsumption, quality of life and/or exercise tolerance are improved bythe administration of at least one hydralazine compound or apharmaceutically acceptable salt thereof and at least one of isosorbidedinitrate and isosorbide mononitrate, and, optionally, one or morecompounds, such as, for example, a digitalis, a diuretic compound,and/or other compounds used to treat cardiovascular diseases. With theadministration of the hydralazine compound (e.g., hydralazine), andisosorbide dinitrate the mortality of black patients was significantlyreduced (p=0.04) in V-HeFT I, whereas white patients showed nodifference from placebo. In V-HeFT II, only white patients exhibited amortality reduction from enalapril compared to the combination ofhydralazine and isosorbide dinitrate (p=0.02). Whites also showedevidence of greater blood pressure reduction and enhanced regression ofcardiac size in response to enalapril. When stratified by history ofhypertension in V-HeFT II, only whites with a history of hypertension,who had higher renin levels, showed significant mortality reduction withenalapril compared to the combination of hydralazine and isosorbidedinitrate. Hospitalization rate did not differ between any treatmentgroup in either study.

[0027] Black and white patients exhibit differences in etiology,neurohormonal stimulation and pharmacologic response in heart failure.The present invention reveals that angiotensin-converting enzyme (ACE)inhibitors are unexpectedly superior in treating white patients, andthat the administration of at least one hydralazine compound and atleast one of isosorbide dinitrate and isosorbide mononitrate isunexpectedly superior in treating African American patients. Forexample, the patient can be administered a hydralazine compound andisosorbide dinitrate, or the patient can be administered a hydralazinecompound and isosorbide mononitrate, or the patient can be administereda hydralazine compound, isosorbide dinitrate and isosorbide mononitrate.Preferably, the patient is administered a hydralazine compound andisosorbide dinitrate.

[0028] This invention for the first time analyzes the baselinecharacteristics and prognosis of a well-defined population of black andwhite patients based on Vasodilator-Heart Failure Trials (V-HeFT I andII) (Cohn et al, N. Engl. J. Med., 314:1547-1552 (1986); Cohn et al, N.Engl. J. Med. 325:303-310 (1991)). Furthermore, since the clinicalresponse of black hypertensive patients to therapy such asangiotensin-converting enzyme (ACE) inhibitors has differed from whites(Br. J. Clin. Pharmac., 14 (Suppl S):97-101 (1982); Saunders et al,Arch. Intern. Med., 150:1710-1713 (1990)) the inventors now, for thefirst time, considered and analyzed differences in the racial responseto the specific therapies within these studies.

[0029] The following definitions are used throughout the specification.

[0030] “Patient” refers to animals, preferably mammals, most preferablyhumans, and includes males and females.

[0031] “Black” refers to a person of African descent or anAfrican-American person.

[0032] “Therapeutically effective amount” refers to the amount of thecompound and/or composition that is effective to achieve its intendedpurpose.

[0033] “Hydralazine compound” refers to a compound having the formula:

[0034] wherein a, b and c are each independently a single or a doublebond; R₁ and R₂ are each independently a hydrogen, an alkyl, an ester ora heterocyclic ring; R₃ and R₄ are each independently a lone pair ofelectrons or a hydrogen, with the proviso that at least one of R₁, R₂,R₃ and R₄ is not a hydrogen. Exemplary hydralazine compounds includebudralazine, cadralazine, dihydralazine, endralazine, hydralazine,pildralazine, todralazine and the like.

[0035] “Alkyl” refers to a lower alkyl group, a haloalkyl group, ahydroxyalkyl group, an alkenyl group, an alkynyl group, a bridgedcycloalkyl group, a cycloalkyl group or a heterocyclic ring, as definedherein.

[0036] “Lower alkyl” refers to branched or straight chain acyclic alkylgroup comprising one to about ten carbon atoms (preferably one to abouteight carbon atoms, more preferably one to about six carbon atoms).Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl,hexyl, octyl, and the like.

[0037] “Haloalkyl” refers to a lower alkyl group, an alkenyl group, analkynyl group, a bridged cycloalkyl group, a cycloalkyl group or aheterocyclic ring, as defined herein, to which is appended one or morehalogens, as defined herein. Exemplary haloalkyl groups includetrifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl,and the like.

[0038] “Alkenyl” refers to a branched or straight chain C₂-C₁₀hydrocarbon (preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆hydrocarbon) which can comprise one or more carbon-carbon double bonds.Exemplary alkenyl groups include propylenyl, buten-1-yl, isobutenyl,penten-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl,hepten-1-yl, octen-1-yl, and the like.

[0039] “Alkynyl” refers to an unsaturated acyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds. Exemplaryalkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl,pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl,hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like.

[0040] “Bridged cycloalkyl” refers to two or more cycloalkyl groups,heterocyclic groups, or a combination thereof fused via adjacent ornon-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridgedcycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl,2,6-dioxabicyclo[3.3.0]octane, 7-oxabycyclo[2.2.1]heptyl,8-azabicyclo[3,2,1]oct-2-enyl and the like.

[0041] “Cycloalkyl” refers to a saturated or unsaturated cyclichydrocarbon comprising from about 3 to about 8 carbon atoms. Cycloalkylgroups can be unsubstituted or substituted with one, two or threesubstituents independently selected from alkyl, alkoxy, amino,alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, aryl,amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid,alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro.Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta,1,3-dienyl, and thelike.

[0042] “Heterocyclic ring or group” refers to a saturated or unsaturatedcyclic hydrocarbon group having about 2 to about 10 carbon atoms(preferably about 4 to about 6 carbon atoms) where 1 to about 4 carbonatoms are replaced by one or more nitrogen, oxygen and/or sulfur atoms.Sulfur maybe in the thio, sulfinyl or sulfonyl oxidation state. Theheterocyclic ring or group can be fused to an aromatic hydrocarbongroup. Heterocyclic groups can be unsubstituted or substituted with one,two or three substituents independently selected from alkyl, alkoxy,amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino,hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkylcarboxylicacid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylicester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido,alkylcarboxamido, arylcarboxamido, hydrazino, sulfonic acid, sulfonicester, sulfonamido and nitro. Exemplary heterocyclic groups includepyrrolyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl,1,4-dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl,oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl,tetrhydrofuranyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl,oxazolindinyl 1,3-dioxolanyl, 2-imidazonlinyl, imidazolindinyl,2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl,4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl,1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, quinolinyl, andthe like.

[0043] “Aryl” refers to a monocyclic, bicyclic, carbocyclic orheterocyclic ring system comprising one or two aromatic rings. Exemplaryaryl groups include phenyl, pyridyl, napthyl, quinoyl,tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like.Aryl groups (including bicylic aryl groups) can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino,diarylamino, alkylarylamino, hydroxy, carboxyl, carboxylic ester,alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid,arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester,carboxamido, alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary substituted aryl groups includetetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl,arylsulfonyl, and the like.

[0044] “Hydroxy” refers to —OH.

[0045] “Hydroxyalkyl” refers to a hydroxy group, as defined herein,appended to an alkyl group, as defined herein.

[0046] “Alkylcarbonyl” refers to R₅₂—C(O)—, wherein R₅₂ is an alkylgroup, as defined herein.

[0047] “Arylcarbonyl” refers to R₅₅—C(O)—, wherein R₅₅ is an aryl group,as defined herein.

[0048] “Ester” refers to R₅₁C(O)O— wherein R₅₁ is a hydrogen atom, analkyl group, an aryl group, an alkylaryl group, or an arylheterocyclicring, as defined herein.

[0049] “Alkylaryl” refers to an alkyl group, as defined herein, to whichis appended an aryl group, as defined herein. Exemplary alkylaryl groupsinclude benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl, and the like.

[0050] “Arylheterocyclic ring” refers to a bi- or tricyclic ringcomprised of an aryl ring, as defined herein, appended via two adjacentcarbon atoms of the aryl ring to a heterocyclic ring, as defined herein.Exemplary arylheterocyclic rings include dihydroindole,1,2,3,4-tetra-hydroquinoline, and the like.

[0051] “Hydrazino” refers to H₂N—N(H)—.

[0052] “Oxygen consumption” was measured during a progressive maximalbicycle-ergometer exercise test taken while the expired air wascollected continuously to monitor oxygen consumption. Dyspnea or fatigueoccurred at a peak oxygen consumption of <25 ml per kilogram of bodyweight per minute. Patients with pulmonary diseases, obstructivevalvular diseases and the like, tend to have a low oxygen consumption.An increase in a patient's oxygen consumption typically results in thepatient's increased exercise tolerance and implies that the patientwould have an improved quality of life.

[0053] “Quality of life” refers to one or more of a persons ability towalk, climb stairs, do errands, work around the house, participate inrecreational activities, and/or not requiring rest during the day,and/or the absence of sleeping problems or shortness of breath. Thequality of life was measured using the Heart Condition Assessment (HCA)questionnaire. The questionnaire was self-administered after briefstandardization instructions. The score was obtained by summing theranks of the responses to each question.

[0054] “Compound used to treat a cardiovascular disease” refers to anytherapeutic compound used to treat any cardiovascular disease. Suitablecompounds include, but are not limited to, angiotensin-converting enzyme(ACE) inhibitors (such as, for example, alacepril, benazepril,captopril, ceronapril, cilazapril, delapril, duinapril, enalapril,enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, pentopril,perindopril, quinapril, ramipril, rentiapril, spirapril, temocapril,trandolapril, zofenopril, and the like); beta-adrenergic blockers (suchas, for example, amosulalol, atenolol, betaxolol, bethanidine,bevantolol, bisoprolol, bopindolol, bucindolol, bufuralol, bunitrolol,bupranolol, butafilolol, carazolol, carteolol, carvedilol, celiprolol,cetamolol, dilevalol, epanolol, indenolol, mepindolol, metipranolol,metoprolol, moprolol, nadolol, nebivolol, nipradilol, penbutolol,pindolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and the like); cholesterolreducers (such as, for example, lovastatin (MEVACOR®), simvastatin(ZOCOR®), pravastatin (PRAVACHOL®), fluvastatin, cerivastatin (BAYCOL®),atorvastatin (LIPITOR®), and the like); calcium channel blockers (suchas, for example, amlodipine, aranidipine, barnidipine, benidipine,cilnidipine, clentiazem, diltiazen, efonidipine, fantofarone,felodipine, isradipine, lacidipine, lercanidipine, manidipine,mibefradil, nicardipine, nifedipine, nilvadipine, nisoldipine,nitrendipine, semotiadil, veraparmil, and the like); angiotensin IIreceptor antagonists (such as, for example, ciclosidomine, eprosartan,furosemide, irbesartan, losartan, saralasin, valsartan, and the like);endothelin antagonists (such as, for example, bosentan, sulfonamideendothelin antagonists, BQ-123, SQ 28608, and the like); and mixturesthereof. The preferred compound used to treat cardiovascular diseases isenalapril.

[0055] “Cardiovascular diseases” refers to any cardiovascular disease,including but not limited to, congestive heart failure, hypertension,pulmonary hypertension, myocardial and cerebral infarctions,atherosclerosis, atherogenesis, thrombosis, ischemic heart disease,post-angioplasty restenosis, coronary artery diseases, renal failure,stable, unstable and variant (Prinzmetal) angina, atherosclerosis,cardiac edema, renal insufficiency, nephrotic edema, hepatic edema,stroke, and the like.

[0056] In the present invention, the preferred hydralazine compound ishydralazine, which is preferably administered in the form of apharmaceutically acceptable salt and most preferably in the form ofhydralazine hydrochloride. Hyralazine hydrochloride is commerciallyavailable from, for example, Lederle Standard Products, Pearl River,N.Y.; and Par Pharmaceuticals Inc., Spring Valley, N.Y.

[0057] Isosorbide dinitrate is commercially available, for example,under the trade names DILATRATE®-SR (Schwarz Pharma, Milwaukee, Wis.);ISORDIL® and ISORDILR TITRADOSE® (Wyeth Laboratories Inc., Philadelphia,Pa.); and SORBITRATE® (Zeneca Pharmaceuticals, Wilmington, Del.).

[0058] Isosorbide mononitrate is commercially available, for example,under the trade names IMDUR® (A. B. Astra, Sweden); MONOKET® (SchwarzPharma, Milwaukee, Wis.); and ISMO® (Wyeth-Ayerst company, Philadephia,Pa.).

[0059] The isosorbide dinitrate and isosorbide mononitrate can bestabilized to prevent explosions by the addition of compounds, such as,but not limited to, lactose, arginine, and the like, and mixturesthereof.

[0060] The hydralazine compound and at least one of isosorbide dinitrateand isosorbide mononitrate can be administered as separate components oras components of the same composition. When the hydralazine compound andat least one of isosorbide dinitrate and isosorbide mononitrate areadministered as separate components, they are preferably administered tothe patient at about the same time. “About the same time” means thatwithin about thirty minutes of administering one compound (e.g., thehydralazine compound or isosorbide dinitrate/mononitrate) to thepatient, the other compound (e.g., isosorbide dinitrate/mononitrate orthe hydralazine compound) is administered to the patient. “About thesame time” also includes simultaneous administration of the compounds.

[0061] In addition to the administration of the combination ofhydralazine compound and at least one of isosorbide dinitrate andisosorbide mononitrate for the treatment of heart failure, and/or forimproving oxygen consumption, quality of life and/or exercise tolerance,the patients can also be administered digitalis, such as, for example,digoxin, and/or diuretics and/or a compound used to treat cardiovasculardiseases. The digoxin is administered preferably orally to achieve asteady state blood serum concentration of at least about 0.7 nanogramsper ml to about 2.0 nanograms per ml. The diuretic is administered,preferably orally, to manage edema. Suitable diuretics include, but arenot limited to, thiazides (such as, for example, chlorothiazide,hydrochlorothiazide), ethacrynic acid, furosemide, spironalactone,triamterene or mixtures thereof. Depending on the diuretic employed,potassium may also be administered to the patient in order to optimizethe fluid balance while avoiding hypokalemic alkalosis. Theadministration of potassium can be in the form of potassium chloride orby the daily ingestion of foods with high potassium content such as, forexample, bananas or orange juice. The method of administration of thesecompounds is described in further detail in U.S. Pat. No. 4,868,179, thedisclosure of which is incorporated by reference herein in its entirety.

[0062] The compounds and compositions of the present invention can beadministered by any available and effective delivery system including,but not limited to, orally, bucally, parenterally, by inhalation spray,or rectally in dosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. The preferred methods of administration are by oraladministration.

[0063] Solid dosage forms for oral administration can include capsules,tablets, chewable tablets, effervescent tablets, pills, powders,granules and gels. In such solid dosage forms, the active compounds canbe admixed with at least one inert diluent such as sucrose, lactose orstarch. Such dosage forms can also comprise, as is normal practice,additional substances other than inert diluents, e.g., lubricatingagents, such as magnesium stearate. In the case of capsules, tablets,effervescent tablets, and pills, the dosage forms can also comprisebuffering agents. Soft gelatin capsules can be prepared to contain amixture of the active compound or composition and vegetable oil. Hardgelatin capsules can contain granules of the active compound incombination with a solid, pulverulent carrier, such as lactose,saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin,or cellulose derivatives of gelatin. Tablets and pills can be preparedwith enteric coatings.

[0064] Liquid dosage forms for oral administration can includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions can also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring,and perfuming agents.

[0065] Suppositories for administration of the compounds or compositionscan be prepared by mixing the drug with a suitable nonirritatingexcipient such as cocoa butter and polyethylene glycols which are solidat room temperature but liquid at body temperature, such that they willmelt in the body and release the drug.

[0066] The term parenteral includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. Injectable preparations, for example, sterile injectableaqueous or oleaginous suspensions can be formulated according to theknown art using suitable dispersing agents, wetting agents and/orsuspending agents. The sterile injectable preparation can also be asterile injectable solution or suspension in a nontoxic parenterallyacceptable diluent or solvent, for example, as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that can beused are water, Ringer's solution, and isotonic sodium chloridesolution. Sterile fixed oils are also conventionally used as a solventor suspending medium.

[0067] The compounds and compositions of the present invention can beformulated as pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts include, for example, alkali metal salts and additionsalts of free acids or free bases. The nature of the salt is notcritical, provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic, hydroiodic,nitrous (nitrite salt), nitric (nitrate salt), carbonic, sulfuric,phosphoric acid, and the like. Appropriate organic acids include, butare not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic,carboxylic and sulfonic classes of organic acids, such as, for example,formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesuifonic, sulfanilic, stearic, algenic,β-hydroxybutyric, cyclohexylaminosulfonic, galactaric and galacturonicacid and the like. Suitable pharmaceutically-acceptable base additionsalts include, but are not limited to, metallic salts made fromaluminum, calcium, lithium, magnesium, potassium, sodium and zinc ororganic salts made from primary, secondary and tertiary amines, cyclicamines, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine and the like. All of these salts may be prepared byconventional means from the corresponding compound by reacting, forexample, the appropriate acid or base with the compound.

[0068] Various delivery systems are known and can be used to administerthe compounds or compositions of the present invention, including, forexample, encapsulation in liposomes, microbubbles, emulsions,microparticles, microcapsules and the like. The required dosage can beadministered as a single unit or in a sustained release form.

[0069] While individual needs may vary, determination of optimal rangesfor effective amounts of the compounds and/or compositons is within theskill of the art. Generally, the dosage required to provide an effectiveamount of the compounds and compositions, which can be adjusted by oneof ordinary skill in the art, will vary depending on the age, health,physical condition, sex, diet and medical condition of the patient, theseverity of the cardiovascular disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compound used,whether a drug delivery system is used, and whether the compound isadministered as part of a drug combination.

[0070] In preferred embodiments, the hydralazine hydrochloride isadministered in an amount of about 30 milligrams per day to about 300milligrams per day; the isosorbide dinitrate is administered in anamount of about 20 milligrams per day to about 200 milligrams per day;and the isosorbide mononitrate is administered in an amount of about 10milligrams per day to about 120 milligrams per day. The preferredamounts of hydralazine hydrochloride, isosorbide dinitrate or isosorbidemononitrate can be administered as a single dose once a day; in multipledoses several times throughout the day; or in a sustained-releaseformulation.

[0071] The amount of a given compound of the present invention whichwill be effective will depend on the nature of the disorder orcondition, and can be determined by standard clinical techniques,including reference to Goodman and Gilman, supra; The Physician's DeskReference, Medical Economics Company, Inc., Oradell, N.J., 1995; andDrug Facts and Comparisons, Inc., St. Louis, Mo., 1993. The precise doseto be used in the formulation will also depend on the route ofadministration, and the seriousness of the disease or disorder, andshould be decided by the physician and the patient's circumstances.

[0072] The present invention also provides pharmaceutical kitscomprising one or more containers filled with one or more of theingredients of the pharmaceutical compounds and/or compositions. Suchkits can also include, for example, other compounds and/or compositions(e.g., diuretics, digoxin, compounds used to treat cardiovasculardiseases and the like), a device(s) for administering the compoundsand/or compositions, and written instructions in a form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which instructions can alsoreflects approval by the agency of manufacture, use or sale for humanadministration.

EXAMPLES

[0073] Statistical Methods

[0074] Baseline measurements were restricted to the test done at thetime of randomization. Change in measurements from baseline werecompared between black and white patients using t-tests performed foreach scheduled follow-up. Kaplan-Meier cumulative mortality curves wereplotted to the end of follow-up to describe the trends in mortality overtime for black and white patients. Survival curves were compared by thelog-rank test. Survival in black and white patients was further analyzedby presence or absence of a history of hypertension.

[0075] In the present invention, an interaction analysis between raceand treatment was performed for both V-HeFT I and II, adjusting forbaseline imbalances.

[0076] Male patients were screened for participation in the study on thebasis of a history of heart failure or documentation of left ventricularenlargement or dysfunction by chest radiography, echocardiography orradionuclide ventriculography. The specific ventricular imagingrequirement for entry was one of the following: a radiographiccardiothoracic ratio >0.55, an echocardiographic left ventricularend-diastolic diameter >2.7 cm/m² body surface area or radionuclide leftventricular ejection fraction <0.45. In addition, patients were eligiblefor entry only if they had reduced maximal exercise tolerance. This wasdefined as a measured peak oxygen consumption (VO₂)<25 ml/kg per minduring a progressive bicycle ergometer exercise test.

[0077] Further details of the V-HeFT trials design, conduct and resultshave been published previously (Cohn et al, N. Engl. J. Med.,314:1547-1552 (1986); Cohn et al, N. Engl. J. Med. 325:303-310 (1991)).V-HeFT I was conducted between 1980 and 1985, prior to the introductionof ACE inhibitor therapy. V-HeFT II was conducted from 1985 to 1990. Inpatients entering V-HeFT II, a venous blood sample was obtained formeasurement of plasma norepinephrine (PNE) and plasma renin activity(PRA) (Core Laboratory, University of Minnesota, Minneapolis, Minn.)after the patient had rested supine for at least 30 minutes. PNE wasmeasured by radioenzymatic assay (Passon et al, Anal. Biochem.,51:618-631 (1973)) and PRA by radioimmunoassay (Sealy et al, KidneyInt'l ., 240-253 (1992)).

[0078] Nearly all patients were receiving background therapy withdiuretic and/or digoxin. They were randomized to receive placebo oractive drug in V-HeFT I and either of two active drugs in V-HeFT II.Full doses of the vasodilator regimens in V-HeFT I were prazosin 5 mgfour times daily, the combination of hydralazine 75 mg and isosorbidedinitrate 40 mg four times daily, or placebo. The V-HeFT II participantsreceived either the same combination of hydralazine and isosorbidedinitrate, (H—I) regimen or enalapril 10 mg twice daily. Drugadministration was double-blind. All patients were studied for theduration of the trial and for a minimum of 6 months or until death.

[0079] Results

[0080] In V-HeFT I, 642 male patients with predominantly New York HeartAssociation class II-III heart failure were enrolled. There were 180black patients and 450 white patients with complete baseline data.V-HeFT II enrolled 804 male patients with 215 black patients and 574white patients having complete baseline data.

[0081] Baseline Characteristics

[0082] Demographics

[0083] Baseline characteristics in V-HeFT I are indicated in Table 1. Incomparison to white patients, black patients were younger with lesshistory of coronary artery disease (CAD). Black patients more commonlyhad a history of hypertension (p<0.05) and a larger cardiothoracic ratio(CTR) (p<0.01). Baseline characteristics in V-HeFT II are shown in Table2. Black patients again less commonly had a history of CAD and morecommonly a history of hypertension (p<0.01) than white patients. Theyalso had lower functional capacity (MVO₂) and larger CTR (p<0.05).

[0084] Neurohormones

[0085] Neurohormonal activation was measured in V-HeFT II. Due to thewide range of values which produced a skewed distribution, values areexpressed as medians with confidence intervals. Plasma renin activity(PRA) in white patients overall did not differ significantly from thatof black patients, (7.3 ng/ml/hr [3.9-17.7] vs 6.55 ng/ml/hr [3.4-12.7](p=0.10). White patients had higher plasma norepinephrine (PNE) thanblack patients (504[368-693] vs 449[330-602] pg/ml, p<0.003).

[0086] Since PRA has been noted to differ by race in hypertensivepatients, we analyzed baseline characteristics including PRA and PNE inV-HeFT II by race in patients with and without a hypertensive history(Table 3). Both black and white patients with a hypertensive history hadhigher ejection fractions and higher systolic and diastolic bloodpressure than patients without a hypertensive history (p<0.02). Whitepatients with a history of hypertension had a higher PRA than blackpatients with a hypertensive history in analysis of median values(p=0.02). PNE did not differ.

[0087] Mortality

[0088] The placebo group mortality in V-HeFT I did not differ betweenwhite and black patients. There were 85 deaths among 192 white placebopatients (annual mortality rate [AMR] 18.8% and 35 deaths among 79 blackplacebo patients (AMR 17.3%) (p=NS) (FIG. 1). The inventors unexpectedlydiscovered that black patients exhibited a significant survival benefitin V-HeFT I from treatment with the combination of hydralazine andisosorbide dinitrate (FIG. 2A). There were 15 deaths among 49 blackpatients treated with the combination of hydralazine and isosorbidedinitrate (AMR 9.7%) compared to 35 of 79 patients in the placebo group(AMR 17.3%) (log-rank p=0.04). There were 21 deaths among 52 patientstreated with prazosin (AMR 15.4) (p=NS compared to placebo). For whitepatients no treatment effect was demonstrated (FIG. 2B). Of 132 patientsrandomized to the combination of hydralazine and isosorbide dinitrategroup, 56 died (AMR 16.9%) whereas 68 died among 127 white patientstreated with prazosin (AMR 22.1%) and 85 of 192 in the placebo group(AMR 18.8%) (p=NS). To further assess the relation between race andtreatment with the combination of hydralazine and isosorbide dinitrate,and placebo, an interaction analysis was undertaken. This difference incongestive heart failure mortality corresponds to a risk ratio of 0.534for mortality when comparing hydralazine and isosorbide dinitrate toplacebo and was significant at p=0.043. The V-HeFT I mortality data werealso analyzed after risk adjustment for differences in baselinecharacteristics. This adjustment further lowered the hydralazine andisosorbide dinitrate to placebo risk ratio to 0.341, p=0.004.

[0089] Cumulative mortality curves by treatment in V-HeFT II are shownin FIGS. 3A and 3B. In the enalapril group, 39 of 106 black patientsdied (AMR 12.8%) compared to 39 of 109 black patients treated with thecombination of hydralazine and isosorbide dinitrate, (AMR 12.9%) (p=NS).For white patients, 90 of 292 treated with enalapril died (AMR 11.0%)whereas 112 of 282 treated with the combination of hydralazine andisosorbide dinitrate died (AMR 14.9%) (log rank p=0.02). A trend for asignificant interaction between race and treatment was demonstrated(p=0.09).

[0090] White patients with a history of hypertension had a significantmortality reduction with enalapril compared to the combination ofhydralazine and isosorbide dinitrate, (p<0.02). Mortality reduction withenalapril did not differ in whites or blacks without hypertensivehistory or in blacks with hypertensive history (FIG. 4).

[0091] There was no difference in the number of patients hospitalized orthe frequency of hospitalization for heart failure or all causehospitalization between black and white patients or between treatmentgroups in either V-HeFT I or II (Table 4).

[0092] Physiologic Changes During Follow-Up

[0093] In order to evaluate whether the race-related differences inoutcome response to treatment were accompanied by differences inphysiologic end-point responses, V-HeFT II data were analyzed regardingenalapril vs the combination of hydralazine and isosorbide dinitrate,effects on blood pressure, left ventricular ejection fraction, peakexercise oxygen consumption, PNE and radiographic CTR.

[0094] Blood Pressure (FIG. 5)

[0095] The initial fall in systolic blood pressure was greater inresponse to enalapril than to the combination of hydralazine andisosorbide dinitrate in both racial groups; however, blood pressurerecovered by 13 weeks in the black patients and remained lowerthereafter in the white patients during the 4.5 years of follow-up. Theeffect of the combination of hydralazine and isosorbide dinitrate, wasstatistically insignificant and similar in both racial groups.

[0096] Ejection Fraction (EF) (FIG. 6)

[0097] Radionuclide EF rose in response to both enalapril and thecombination of hydralazine and isosorbide dinitrate in both racialgroups. The increase for the first year in response to the combinationof hydralazine and isosorbide dinitrate tended to be greater than toenalapril in both groups. Since survival was better in the whiteenalapril group, the magnitude of the late response may be influenced bysurvival of higher risk patients in that group.

[0098] Exercise Tolerance (MVO₂) (FIG. 7)

[0099] Peak exercise oxygen consumption was monitored sequentially at 13weeks and then at 6-month intervals throughout the study. Enalapril didnot improve oxygen consumption (MVO₂) in either racial group whereas thecombination of hydralazine and isosorbide dinitrate increased it in bothblack and white patients at 13 weeks. A comparison between thehydralazine and isosorbide dinitrate group and placebo group in V-HeHT Ifor the change from baseline in MVO₂ at 12 months approached statisticalsignificance. Black patients on hydralazine and isosorbide dinitrateexperienced a 0.962 ml/kg/min mean increase in MVO₂, whereas thepatients on placebo experienced a 0.177 ml/kg/min decrease in MVO₂ overthe same period, p=0.162. The corresponding values adjusted for baselinecharacteristics were 1.25 ml/kg/min increase for hydralazine andisosorbide dinitrate and a 0.394 ml/kg/min decrease for placebo,p=0.068. Longitudinal models were fit to examine MVO₂ differences overthe first year of V-HeFT I. These models indicated a similar trend asabove, with black patients on hydralazine and isosorbide dinitratehaving greater MVO₂ than black patients on placebo, p=0.11. Hydralazineand isosorbide dinitrate clinically and statistically improved exercisetolerance as assessed by MVO₂.

[0100] There was a significant difference in the effects of hydralazineand isosorbide dinitrate and enalapril on the response to the HeartCondition Assessment (HCA) questionnaire on quality of life in blackpatients in V-HeFT II. Hydralazine and isosorbide dinitrateprogressively improved quality of life scores in black patients,attaining a value of −0.67 at 12 months. Over the same period enalaprilworsened quality of life scores, up to a value of +1.04. This differencewas significant, p=0.043.

[0101] The surrogate endpoint of MVO₂ at 12 months differedsignificantly between the hydralazine and isosorbide dinitrate group andthe enalapril group. Black patients on hydralazine and isosorbidedinitrate experienced a 0.602 ml/kg/min mean improvement from baselinein MVO₂ versus a 0.047 ml/kg/min decrease for enalapril, p=0.19.Following adjustment for differences in baseline characteristics, blackpatients on hydralazine and isosorbide dinitrate experienced a 0.787ml/kg/min mean improvement from baseline in MVO₂ versus a 0.010ml/kg/min increase for enalapril patients, p=0.15. MVO₂ was alsoanalyzed using a longitudinal model that took into account all MVO₂ datacollected over the entire 12 months. In this analysis, hydralazine andisosorbide dinitrate performed better than enalapril from baseline,p=0.084 unadjusted and p=0.067 risk-adjusted. The improvement inexercise tolerance associated with hydralazine and isosorbide dinitrate,as measured by MVO₂, is clinically significant and approachesstatistical significance.

[0102] Plasma Norepinephrine (FIG. 8)

[0103] The increase in PNE observed in response to the combination ofhydralazine and isosorbide dinitrate, was not apparent in response toenalapril in either racial group. No racial difference in response wasdetected.

[0104] Cardiothoracic Ratio (FIG. 9)

[0105] A significant reduction in radiographic heart size was notedduring follow-up in white patients in both treatment groups. Thebeneficial effect of enalapril persisted through 3 years whereas thebenefit of the combination of hydralazine and isosorbide dinitrate wasno longer significant after the first year. Black patients exhibited nosignificant heart size reduction with either treatment.

[0106] Discussion

[0107] In the present invention, the inventors analyzed data from V-HeFTI and V-HeFT II to determine whether there was a significant baselinedifference between black and white patients with heart failure, and todetermine whether race has an impact on mortality reduction, oxygenconsumption, exercise tolerance and quality of life observed withvasodilator and ACE inhibitor therapy. It has now been discovered thatthe combination of at least one hydralazine compound and at least one ofisosorbide dinitrate and isosorbide mononitrate, and, optionally, one ormore compounds, such as, for example, a digitalis, a diuretic compound,and/or a compound used to treat cardiovascular diseases has anunexpectedly superior effect in prolonging survival and improving oxygenconsumption, exercise tolerance and quality of life in black patients.This combination is equally effective as enalapril in this subgroup. Incontrast, enalapril exhibits its more favorable effect on survivalparticularly in the white population.

[0108] Since V-HeFT I compared the combination of hydralazine andisosorbide dinitrate to placebo and V-HeFT II compared enalapril and thecombination of hydralazine and isosorbide dinitrate, without a placeboarm, it is not possible to determine whether the racial influence on themortality reduction from ACE inhibitors is due to a reduced effect ofACE inhibitors in the black population or a greater response to thecombination of hydralazine and isosorbide dinitrate in that population.The non-sustained blood pressure reduction observed in response toenalapril in the black population compared to the white populationsuggests that at least some of the differential outcome response toV-HeFT II can be attributed to lesser ACE inhibitor effect in blackpatients.

[0109] Although not addressed, the data clearly suggest less efficacy ofenalapril in the black subgroup than in the white subgroup, with ablack:white relative risk of 1.15 in the placebo group and 1.34 in theenalapril group. Nonetheless, the evidence now discovered from V-HeFT Iof the unique and superior efficacy of the combination of hydralazineand isosorbide dinitrate in the black population suggests that thisracial difference in efficacy also contributed to the similar effects ofACE inhibitor and the combination of hydralazine and isosorbidedinitrate in the black patients.

[0110] It is important to examine the baseline differences between blackand white patients to explore the possible interaction of thesedifferences on the response to therapy. As noted in previous studies,blacks had a lower incidence than whites of CAD (Peniston et al, J. Am.Coll. Cardiol., 299A (1994); Joint National Committee, Arch Intern Med,144:1045-1057 (1985)), and a higher incidence of prior hypertension.(Joint National Committee, Arch. Intern. Med., 144:1045-1057 (1985);Bourassa et al, J. Am. Coll. Cardiol., 22(Suppl A):14-19 (1993)). InV-HeFT, blacks demonstrated a larger radiographic cardiothoracic ratioand a non-significant trend for a higher ejection fraction, and theejection fraction was significantly higher in blacks than in whites witha hypertensive history, the group in whom the racial differences inresponse to ACE inhibition was most prominent. Although we cannotexclude that baseline differences in the prevalence of diastolicdysfunction or other variables could have contributed to the apparentracial differences in response, prior analysis has demonstrated asimilar response to therapy in subgroups based on etiology, hypertensionhistory, cardiothoracic ratio and ejection fraction (Cohn et al,Circulation, (Suppl VI); 75:49-54 (1987); Johnson et al, Circulation,87(Suppl VI): 32-39 (1993).

[0111] The finding that mortality and morbidity as represented by CHFhospitalizations are similar in blacks and whites with heart failure isat variance with previous reports. Ghali et al (Arch. Intern. Med.,150:769-773 (1990)) reported that non-white men were more commonlyhospitalized for heart failure. In a previous analysis Ghali et al(Arch. Intern. Med., 148:2013-2106 (1988)) had indicated thatuncontrolled hypertension was present in 44% of non-white patientswhereas 64% were non-compliant with medications. Alexander et al (JAMA,274(13):1037-1042 (1995)) analyzed an Health Maintenance Organization(HMO) database and found that black males and females were at greaterrisk of CHF hospitalization; however in males this excess risk couldlargely be accounted for by clinical variables including hypertension.Bourassa et al (J. Am. Coll, Cardiol., 22(Suppl A):14-19, 1993)) alsoreported from the SOLVD Registry that blacks had a greater incidence ofhospitalization, but a similar mortality to that in whites. In contrast,the National Center for Health Statistics in the United States (N. Engl.J. Med., 329:621-627 (1993)) reported higher age adjusted death ratesfor blacks compared to whites between 1970 and 1985, a time periodlargely before the SOLVD and V-HeFT trials were conducted.

[0112] The present invention addresses a much different population.Hypertension, often uncontrolled, was common in the Ghali and Alexanderdatabases whereas currently hypertensive patients were excluded fromV-HeFT. Patients were closely followed in V-HeFT by protocol, usually bythe same investigator team. The follow-up certainly differed from thelarge population database retrospectively examined by Ghali andAlexander as well as from the SOLVD Registry. A plausible explanation isthat when access to resources is equal and there is close follow-up, nodifference in mortality or hospitalizations will be observed betweenblacks and whites.

[0113] Neurohormonal Mechanisms

[0114] Prior studies in hypertension have suggested that reducedresponsiveness to ACE inhibitors may be attributed to a lower PRA in theblack population population. Indeed, the differential benefit in V-HeFTII of ACE inhibitor therapy in whites compared to blacks wasparticularly prominent in those with a prior history of hypertension inwhom PRA was significantly lower in blacks than in whites.

[0115] The mechanism of PRA stimulation in heart failure remainscontroversial. Diuretics, which were being administered chronically innearly all the patients, may be partly responsible for the reninstimulation, (Cody et al, J. Clin. Invest., 77:1441-1452 (1986)) but PRAvalues were elevated in untreated patients as well. (Anand et al,Circulation, 78:11-106 (1988). Why black patients with heart failure anda hypertensive history exhibit less renin response than their whitecounterparts remains uncertain but is consistent with previousobservations of less renin response to furosemide in the blackpopulation. (Kaplan et al, Annals of Internal Medicine, 84:639-645(1976)). It is also unclear why PRA was not lower in the black than thewhite heart failure population without a history of hypertension, butthis observation raises interesting speculations about a possiblegenetic difference between black individuals with and without a historyof hypertension.

[0116] The slightly lower PNE level in black compared to white patientsin V-HeFT II has not previously been noted in a heart failurepopulation. The difference could reflect a less severe heart failuresyndrome in blacks and their EF, an important determinant of survival,(Cohn et al, Circulation, 87(Suppl VI):5-16 (1993)) was significantlyhigher. Nonetheless, the similar mortality observed in the two racialsubgroups does not support the hypothesis that blacks were less sick.Previous data indicate that plasma epinephrine in black adults andurinary norepinephrine in black children are lower than in whites (Millset al, Hypertension, 25:88-91 (1995); Pratt et al, J. Hypertension,January 10:93-96 (1992)). Mills et al (Hypertension, 25:88-91 (1995))also reported that blacks had increased beta receptor number andsensitivity which could account for lower circulating levels. How theseobservations apply to patients with heart failure, whose sympatheticnervous system is stimulated by a variety of afferent signals, remainsuncertain.

[0117] Implications of Differential Response to Therapy

[0118] The differential pharmacologic response that has now beendiscovered between black and white patients from V-HeFT is consistentwith the previously described differential antihypertensive effects,with blacks less responsive to ACE inhibitors (Br. J. Clin. Pharmac.,14(Suppl S):97-101 (1982); Saunders et al, Arch. Intern Med.,150:1710-1713 (1990)) and beta blockers (JAMA, 248:1996-2003 (1982);JAMA, 248:2004-2011 (1982)). When compared to the effect of thecombination of hydralazine and isosorbide dinitrate, the greatermortality reduction in V-HeFT with ACE inhibitors in whites than inblacks raises the possibility that surveys of heart failure outcome inACE inhibitor-treated patients might reveal a poorer prognosis in theblack population.

[0119] Without intending to be bound by any theory of the invention,reduced efficacy of ACE inhibitors in blacks appears to be related inpart to a less active renin-angiotensin system in blacks. Thisobservation is consistent with the concept of Cody et al (Hypertension,5 (Suppl III):36-42, (1983)) that PRA activity is predictive of ACEinhibitor efficacy in both hypertension and heart failure. A racialdifference in the effect of ACE inhibitors on blood pressure also wasconfirmed in this study in patients with heart failure. No clearevidence of a racial difference in effect on other physiologicend-points was observed, perhaps because of the modest sample size; butthe benefits of enalapril on PNE and CTR appeared to be most prominentin the white population.

[0120] The unexpected finding of the present invention is that blacksresponded more favorably than whites to the combination of at least onehydralazine compound and either isosorbide dinitrate or isosorbidemononitrate. As this combination exerted a mortality effect similar tothat of enalapril in V-HeFT II, it raises important considerations.Hydralazine was initially combined with isosorbide dinitrate because oftheir additive hemodynamic effects (Pierpont et al., Chest, 73:8-13(1978)). Recent evidence, however, supports an antioxidant effect ofhydralazine to enhance and sustain the efficacy of nitrates (Bauer etal., Circulation, 84:35-39 (1991); MÅzel et al., J. Clin. Invest.,98:1465-1470 (1996); Gogia et al., J. Am. Coll. Cardiol. 26:1575-1580(1995)). The uniquely favorable effect of this combination in blackpatients suggests the possibility that blacks, particularly those with ahypertensive history, may have a greater deficiency of nitric oxidegeneration that is restored by the isosorbide dinitrate and/orisosorbide mononitrate. Similarly, the apparent lesser efficacy ofenalapril in this subgroup suggests that the renin-angiotensin systemmay not be playing as active a role in the black hypertensivepopulation.

[0121] The present finding of a consistency of observations of a racialdifference in response in V-HeFT I and V-HeFT II, buttressed by theapparent racial difference in response in SOLVD and the racialdifference in blood pressure response in V-HeFT II, support thesuggestion that therapy for heart failure, improved oxygen consumption,exercise tolerance and quality of life might appropriately be raciallytailored. ACE inhibitors remain the treatment of choice to prolongsurvival in white patients. The present inventors now discovered thatfor black patients the combination of at least one hydralazine compoundand at least one of isosorbide dinitrate and isosorbide mononitrate isan attractive alternative, since it exerted unexpectedly superiorimprovement in exercise tolerance, quality of life, oxygen consumptionand EF and unexpectedly prolonged survival.

[0122] The disclosure of each patent, patent application and publicationcited or described in the present specification is hereby incorporatedby reference herein in its entirety.

[0123] Although the invention has been set forth in detail, one skilledin the art will appreciate that numerous changes and modifications canbe made to the invention without departing from the spirit and scopethereof. TABLE 1 V-HeFT I - BASELINE VARIABLES Black White (n = 180) (n= 480) Demographics: Age (years) 56.3 ± 9.0 59.2 ± 6.9** CAD (%) 20.853.2** Hx HTN (%) 46.6 37.3 Measurements: SBP sitting (mmHg) 118.0 ±16.4 119.7 ± 19.6  DBP sitting (mmHg) 76.6 ± 9.6 75.6 ± 10.3 Heart Ratesitting (beats/min)  83.1 ± 13.1 81.7 ± 13.3 Ejection Fraction (%)  31.3± 14.1 29.3 ± 12.4 M V O₂ (ml/kg/min) 14.7 ± 4.3 14.7 ± 3.6 Cardiothoracic Ratio (%) 55.0 ± 6.3  52.7 ± 6.3**

[0124] TABLE 2 V-HeFT II - BASELINE VARIABLES Black White (n = 215) (n =574) Demographics: Age (years) 58.8 ± 9.0 61.1 ± 8.0 CAD (%) 28.4 61.6**Hx HTN (%) 64.9 41.5** Measurements: SBP sitting (mmHg) 126.0 ± 16.6126.4 ± 17.3  DBP sitting (mmHg) 79.4 ± 9.4 77.7 ± 9.3  EjectionFraction (%)  29.2 ± 11.5 29.0 ± 11.1 M V O₂ (ml/kg/min) 13.4 ± 3.4 13.9± 3.5* Cardiothoracic Ratio (%) 54.3 ± 6   52.2 ± 6*   PNE (pg/ml) 449(330-602) 504 (368-693)^(+*) PRA (ng/ml/hr) 6.6 (3.4-12.7) 7.3(3.9-17.7)⁺

[0125] TABLE 3 BASELINE CHARACTERISTICS W (+HTN) W (−HTN) B (+HTN) B(−HTN) (218) (318) (132) (72) PRA 8.1 6.8 6.2 7.0 ng m1⁻¹hr⁻¹ (4-18.2)†(3.8-16.1) (3.3-12.7) (4.6-15.8) PNE 497 510 469 437 (366-659 (373-729)(329-601) (333-621) EF %   31 ± 11.8‡ 27.6 ± 10.4 30.7 ± 12‡  26.6 ±10.4 CTR 0.52 ± 0.06 0.52 ± 0.06 0.54 ± 0.06 0.54 ± 0.06 M V O₂ 13.6 ±3.3    14 ± 3.6 13.6 ± 3.5  12.7 ± 3.3  m1 kg⁻¹ min⁻¹ SBP 133 ± 17‡   122 ± 15   129 ± 17‡    121 ± 15 mmHg DBP 80 ± 9‡     75 ± 9    81 ±10‡     77 ± 9 mmHg

[0126] TABLE 4 HOSPITALIZATION V-HeFT I White Placebo Black n (%)Prazosin Hyd-Iso Total Placebo Prazosin Hyd-Iso Total White vs. BlackNumber of patients 49 (25.5) 40 (31.5) 32 (24.2) 121 (26.8) 16 (20.3) 12(23.) 11 (22.4) 39 (21.7) P = 0.18 hospitalized for P = 0.24 P = 0.80 P= 0.70 P = O.77 CHF (%) Number of patients 67 (34.9) 45 (35.4) 56 (42.4)168 (37.3) 39 (49.4) 21 (40.4) 20 (40.8) 80 (44.4) P = 0.10 hospitalizedfor P = 0.93 P = 0.17 P = 0.32 P = 0.35 any reason (%) V-HeFT II WhiteHyd-Iso Black n (%) Enalapril Total Hyd-Iso Enalapril Total White vs.Black Number of patients  51 (18.1)  51 (17.5) 102 (17.8) 23 (21.1) 24(22.6) 47 (21.9) P = 0.20 hospitalized for P = 0.85 P = 0.79 CHF Numberof patients 165 (58.5) 181 (62.0) 346 60.3 59 (54.1) 65 (61.3) 124 57.7P = 0.51 hospitalized for P = 0.40 P = 0.29 any reason

What is claimed is:
 1. A kit comprising hydralazine or apharmaceutically acceptable salt thereof, isosorbide dinitrate, andwritten instructions in a form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals or biologicalproducts, for administration to a black patient.
 2. The kit of claim 1,further comprising at least one compound selected from a digitaliscompound, a diuretic compound, and a compound used to treat acardiovascular disease.
 3. The kit of claim 1, further comprising one ormore compounds selected from the group consisting of a digitaliscompound, a diuretic compound, potassium, an angiotensin-convertingenzyme inhibitor, a beta-adrenergic blocker, a cholesterol reducer, acalcium channel blocker, an angiotensin II receptor antagonist, and anendothelin antagonist.
 4. The kit of claim 1, wherein the hydralazine orthe pharmaceutically acceptable salt thereof and the isosorbidedinitrate are separate components in the kit or are in the form of acomposition in the kit.
 5. A kit comprising at least one hydralazinecompound of Formula (I), or a pharmaceutically acceptable salt thereof,at least one of isosorbide dinitrate and isosorbide mononitrate, andwritten instructions in a form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals or biologicalproducts, for administration to a black patient; wherein the hydralazinecompound of Formula (I) is:

wherein a, b and c are each independently a single or a double bond; R₁and R₂ are each independently a hydrogen, an alkyl, an ester or aheterocyclic ring; R₃ and R₄ are each independently a lone pair ofelectrons or a hydrogen, with the proviso that at least one of R₁, R₂,R₃ and R₄ is not a hydrogen.
 6. The kit of claim 5, further comprisingat least one compound selected from a digitalis compound, a diureticcompound, and a compound used to treat a cardiovascular disease.
 7. Thekit of claim 5, further comprising one or more compounds selected fromthe group consisting of a digitalis compound, a diuretic compound,potassium, an angiotensin-converting enzyme inhibitor, a beta-adrenergicblocker, a cholesterol reducer, a calcium channel blocker, anangiotensin II receptor antagonist, and an endothelin antagonist.
 8. Thekit of claim 5, wherein the at least one hydralazine compound or thepharmaceutically acceptable salt thereof and at least one of isosorbidedinitrate and isosorbide mononitrate are separate components in the kitor are in the form of a composition in a kit.
 9. A method of reducingmortality associated with heart failure in a black patient in needthereof comprising administering to the black patient hydralazine or apharmaceutically acceptable salt thereof in an amount of about 30milligrams per day to about 300 milligrams per day and isosorbidedinitrate in an amount of about 20 milligrams per day to about 200milligrams per day.
 10. A method for improving oxygen consumption in ablack patient in need thereof comprising administering to the blackpatient hydralazine or a pharmaceutically acceptable salt thereof in anamount of about 30 milligrams per day to about 300 milligrams per dayand isosorbide dinitrate in an amount of about 20 milligrams per day toabout 200 milligrams per day.
 11. A method of reducing mortalityassociated with heart failure in a black patient comprisingadministering to the black patient a therapeutically effective amountof: (i) at least one hydralazine compound or a pharmaceuticallyacceptable salt thereof; (ii) at least one of isosorbide dinitrate andisosorbide mononitrate; and (iii) optionally, one or more compoundsselected from the group consisting of a digitalis compound, a diureticcompound, potassium, an angiotensin-converting enzyme inhibitor, abeta-adrenergic blocker, a cholesterol reducer, a calcium channelblocker, an angiotensin II receptor antagonist, and an endothelinantagonist.
 12. The method of claim 11, wherein the black patient hashypertension.
 13. The method of claim 11, wherein the hydralazinecompound is budralazine, cadralazine, dihydralazine, endralazine,hydralazine, pildralazine, todralazine or a pharmaceutically acceptablesalt thereof.
 14. The method of claim 11, wherein the hydralazinecompound is hydralazine hydrochloride.
 15. The method of claim 11,wherein the at least one hydralazine compound and the at least one ofisosorbide dinitrate and isosorbide mononitrate are administered to theblack patient as components of the same composition or as separatecomponents.
 16. A method for improving oxygen consumption in a blackpatient in need thereof comprising administering to the black patient atherapeutically effective amount of: (i) at least one hydralazinecompound or a pharmaceutically acceptable salt thereof; (ii) at leastone of isosorbide dinitrate and isosorbide mononitrate; and (iii)optionally, one or more compounds selected from the group consisting ofa digitalis compound, a diuretic compound, potassium, anangiotensin-converting enzyme inhibitor, a beta-adrenergic blocker, acholesterol reducer, a calcium channel blocker, an angiotensin IIreceptor antagonist, and an endothelin antagonist.
 17. The method ofclaim 16, wherein the black patient has hypertension.
 18. The method ofclaim 16, wherein the hydralazine compound is budralazine, cadralazine,dihydralazine, endralazine, hydralazine, pildralazine, todralazine or apharmaceutically acceptable salt thereof.
 19. The method of claim 16,wherein the hydralazine compound is hydralazine hydrochloride.
 20. Themethod of claim 16, wherein the at least one hydralazine compound andthe al least one of isosorbide dinitrate and isosorbide mononitrate areadministered to the black patient as components of the same compositionor as separate components.